We search for mutations responsible for inherited neurological and psychiatric disorders, including schizophrenia and bipolar illness. The phenotypic heterogeneity seen within these inherited disorders can be due to involvement of multiple genes or a consequence of different mutations in a single gene, each affecting protein activity and influencing the processing, compartmentalization and/or stability of the protein. In the case of genetic disorders where a protein abnormality has been identified (such as Gaucher disease), southern analysis and polymerase chain amplification is used to identify mutations that occur in non- neuronopathic and neuronopathic phenotypes. The molecular mechanisms leading to nervous system involvement in these disorders are also studied. The results of this research should provide a molecular basis for diagnosis and formulation of additional therapeutic strategies for these inherited disorders. Genes that may be involved in neuropsychiatric disorders, such as those for neurotransmitter biosynthesis (for example, human tyrosine hydroxylase and tryptophan hydroxylase) are isolated and characterized. Using restriction length fragment polymorphisms (RFLP) and microsatellite DNA markers spaced at 10-20 centiMorgan intervals, we are genotyping individuals in an Old Order Amish pedigree and performing linkage analysis in order to identify gene loci responsible for bipolar illness analysis in order to identify a gene locus responsible for bipolar illness (see Project # ZO1 MH 02625- 04 NS). Methodologies such as chromosome dissection are being developed that will permit us to generate high resolution physical maps and identify expressed sequences from selected, high interest regions of the genome. Human DNA regions containing trinucleotide repeats are being isolated and characterized, including flanking sequence determination and chromosome location. DNA from individuals affected with a variety of psychiatric disorders is being examined for the occurrence of abnormalities, including trinucleotide repeat expansions, that may identify disease genes.